Basic and Clinical Development of Vaccines and Other Prevention Strategies
against HIV-1
HIV pathogenesis and treatment had been the major areas of study in the past. Since 2001, my laboratory has focused on development of novel vaccines against HIV-1, both in the laboratory and in the clinic. Our first two candidate vaccines were ADVAX, a DNA-based multigenic clade C/B’ DNA-based vaccine, and ADMVA, a multigenic clade C/B’ vaccine utilizing the Modified Vaccinia Ankara virus. These vaccines have completed Phase I clinical testing. In particular, we have explored the delivery of ADVAX using an in vivo electroporation device. We are also developing novel vaccines with improved cellular and humoral immunogenicity by targeting dendritic cells, a project funded by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery.

Our group is now actively designing vaccine constructs that attempt to raise neutralizing antibodies directed to the viral envelope glycoproteins. We are also developing vaccine platform technologies that try to target our immunogens to dendritic cells. Specifically, we are utilizing Fc-fusion and flagellin-fusion approaches to deliver the antigen of interest to dendritic cells via activation Fc receptors and TLR5, respectively.

Another strategy to HIV prevention is to test monoclonal antibodies directed to domain-2 of CD4, the primary receptor for HIV on the surface of target cells. We are now examing an antibody known as ibalizumab to assess its ability to protect against SIV in monkeys and HIV in humans. We are also endeavoring to develop variants of ibalizumab that have improved affinity, pharmacokinetics, and efficacy. Furthermore, we are exploring the use of AAV vector to express this monoclonal antibody to block SIV/HIV transmission.

Our group is also making "fusion" antibody constructs that have multiple antibody variable domains, each of which is capable of blocking a step or a site involved in HIV entry. These biologics could be used for both prophylaxis and treatment.

Our laboratory works to brighten the design and delivery of HIV vaccines to heighten the body’s immune response to these vaccines. One strategy involves designing vaccines to “target” dendritic cells, a specialized immune cell in the body that coordinates many aspects of the immune response. Studies have shown that vaccines targeting dendritic cells elicit a longer and stronger immune response. This work is being sponsored by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery, and is being conducted with a consortium of scientists. Another strategy involves antibodies that could block HIV infection by interfering with the binding to CD4, the receptor for HIV. Our group is also pursuing the use of a monoclonal antibody, known as ibalizumab, in preventing SIV infection in monkeys and HIV infection in humans. Moreover, we are creating novel forms of HIV-inhibitory antibodies that could be used for both prophylaxis and treatment.